N4 Acyl-1-arabinofuranosylcytosine-5&#39;-esters

ABSTRACT

N 4  -Acyl-1-β-D-arabinofuranosylcytosine-5&#39;-esters represented by the formula ##STR1## wherein R 1  represents an acyl group having 3 to 28 carbon atoms and R 2  represents an XCH 2 , XCH 2  CH 2  or CH 3  CHX group, wherein X represents a halogen atom, a (CH 3 ) 2  N or (C 2  H 5 ) 2  N group.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-amino esters havingantileukemial activity and N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-haloesters which areintermediates in the synthesis of the above-describedarabinosuranosylcytosine amino esters.

2. Description of the Prior Art

N⁴ -Acyl-1-β-D-arabinofuranosylcytosines have a remarkable effect aginstL-1210 leukemia in mice, and, among them, those carrying an acyl grouphaving 14 to 22 carbon atoms exhibit particularly remarkable effects.

These N⁴ -acyl-1-β-D-arabinofuranosylcytosines are generally insolubleor only slightly soluble in water, and can be prepared by reactingarabinofuranosylcytosine and an acid anhydride in water and awater-miscible organic solvent, for example, a mixed solvent ofwater-dioxane (1:10 by volume), at a temperature of about 60° C forabout 4 hours.

SUMMARY OF THE INVENTION

An object of this invention is to provide compounds which exhibitexcellent dispersibility in water by chemically modifying N⁴-acyl-1-β-D-arabinofuranosylcytosines.

The inventors performed various investigations to discover moreeffective antileukemial agents by selecting materials which wouldprolong the life of mice infected by L-1210 leukemia, using the methoddeveloped by the Drug Research & Development Department of the NationalCancer Institute of the United States for screening antitumour agentsand antileukemial agents for humans (it has been confirmed from datacollected on a world-wide basis that medicaments effective againstL-1210 leukemia have the greatest possibility of being effectively usedfor the treatment of leukemia in humans) and, as a result, the inventorsfound that novel compounds, N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-amino esters, meet the abovedescribed object, and also discovered novel N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-haloesters which are useful asintermediates therefor.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIG. 1 shows the infrared absorption spectrum of N⁴-stearoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate according tothe present invention.

FIG. 2 shows the ultraviolet absorption spectrum of a solution of N⁴-palmitoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate inmethanol according to the present invention.

FIG. 3 shows the ultraviolet absorption spectrum of a dioxane solutionof N⁴ -margaroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinateaccording to the present invention.

FIG. 4 shows the ultraviolet absorption spectrum of a dioxane solutionof N⁴-stearoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionateaccording to the present invention.

FIG. 5 shows the infrared absorption spectrum of N⁴-stearoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionateaccording to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The N⁴ -acyl-1-β-D-arabinofuranosylcytosine-5'-esters present inventioncan be represented by the formula (I) ##STR2## wherein R¹ represents anacyl group having 3 to 28 carbon atoms, preferably an acyl groupselected from the class consisting of propionyl, butyryl, iso-butyryln-valeryl, isovaleryl, caproyl, heptanoyl, caprylyl, nonanoyl, capryl,undecanoyl, lauroyl, tridecanoyl, myristoyl, tetradecenoyl,pentadecanoyl, palmitoyl, margaroyl, stearoyl, oleoyl, nonadecanoyl,arachidoyl, heneicosanoyl, behenoyl and lignoceroyl, most preferably anacyl group selected from the class consisting of myristoyl,tetradecenoyl, pentadecanoyl, palmitoyl, margaroyl, stearoyl, oleoyl,nonadecanoyl, arachidoyl, heneicosanoyl and behenoyl; and R² representsan XCH₂, XCH₂ CH₂ or CH₃ CHX group wherein X represents a halogen atom,preferably a halogen atom selected from the class consisting of chlorineand bromine, or X represents a (CH₃)₂ N or (C₂ H₅)₂ N group. The N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-haloesters represented byformula (I), wherein X represents a halogen atom, can be used asintermediates for forming the N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-aminoesters represented byformula (I), wherein X represents a (CH₃)₂ N or (C₂ H₅)₂ N group.

N⁴ -Acetyl-1-β-D-arabinofuranosylcytosines of formula (I) wherein R¹ has2 carbon atoms are not included in this invention since the acetyl groupis easily released during the working-up procedures after reaction.

The N⁴ -acyl-1-β-D-arabinofuranosylcytosine-5'-haloacetates and N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-halopropionates according to thepresent invention can be obtained by reacting an N⁴-acyl-1-β-D-arabinofuranosylcytosine with a haloacetyl halide and ahalopropionyl halide, respectively. The halide is advantageously used inan equimolar amount to about 3 molar times bases on the startingmaterial. The halide may be added all at once, but is particularlyadvantageously added in portions over the reaction in order to increasethe yield of the product.

The reaction pressure is, in general, atmospheric pressure. The reactiontemperature is not particularly limited, but generally low temperatures(from room temperature to less than about 50° C) are desirable. Thereaction time is preferably more than about 6 hours and up to about 24hours. It is advantageous to carry out the reaction in an organicsolvent of high polarity, for example, pyridine, acetone,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide and thelike, preferably N,N-dimethylacetamide.

The progress of the esterification can be followed by thin layerchromatography using silica gel and a mixed solvent ofchloroform:methanol (e.g., about 5:1 by volume). After completion of thereaction, any unreacted acid halide can be decomposed with water,thereby precipitating the reaction product. The resulting product can besubjected to the subsequent reaction without purification. However, ifnecessary, purification can be conducted by recrystallization, columnchromatography or the like. Acetone, tetrahydrofuran, ethyl acetate andthe like are used as a solvent for recrystallization. In the case ofcolumn chromatography, silica gel and a mixed solvent ofmethanol:chloroform are used as an adsorbent and a developer,respectively, and the mixing ratio of the methanol:chloroform developeris varied initially from about 1:20, gradually increasing the volume ofmethanol, finally to about 1:5.

The reaction product can be identified by its infrared absorptionspectrum, ultraviolet absorption spectrum and by elementary analysis.

The N⁴ -acyl-1-β-D-arabinofuranosylcytosine-5'-amino esters representedby formula (I) wherein X represents a (CH₃)₂ N or (C₂ H₅)₂ N group canbe prepared by reacting the above described N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-haloester with dimethylamine ordiethylamine in an amount of about 1 to about 10 moles per one mole ofthe N⁴ -acyl-1-β-D-arabinofuranoylcytosine-5'-haloester used. Thereaction temperature is not particularly limited, but generally lowtemperatures (from room temperature to below 0° C) are desirable. Thereaction time ranges from about more than about 5 minutes to about 24hours, preferably 4 to 5 hours, at atmospheric pressure. The reactionmay be conducted without any solvent or in a solvent such as diethylether, tetrahydrofuran, acetone, benzene, n-hexane, chloroform,methylene dichloride, etc., in an amount of about 1 to about 50 molesper one mole of dimethylamine or diethylamine used.

The above reaction may be effected in air, but is advantageouslyconducted under an atmosphere of argon or nitrogen because theworking-up procedures are simpler.

The progress of the amination can be traced by thin layer chromatographyusing silica gel and a mixed solvent of chloroform:methanol (e.g., about5:1 by volume). Confirming that the starting material has disappeared,the resulting amine hydrochloride is filtered, and the solvent and theunreacted amine are distilled off under reduced pressure. The whitepowder thus obtained is then purified by column chromatography usingsilica gel. As a developer, a mixed solvent of methanol:chloroform isemployed varying the mixing ratio thereof initially from about 1:20 bygradually increasing the volume of methanol to a final value of about1:5 by volume.

The reaction product thus obtained can be identified by its infraredabsorption spectrum, ultraviolet absorption spectrum and nuclearresonance absorption spectrum and by elementary analysis.

The present invention will now be illustrated in more detail by severalnon-limiting examples. All processings are at atmospheric pressure,unless otherwise indicated.

EXAMPLE 1

1.01 g of N⁴ -stearoyl-1-β-D-arabinofuranosylcytosine was dissolved in12 ml of N,N-dimethylacetamide, and a solution of 0.24 g of chloroacetylchloride in N,N-dimethylacetamide was added thereto while on anice-water bath followed by stirring for 1 hour at room temperature. Tothe mixture was further added 0.24 g of chloroacetyl chloride followedby stirring for 20 to 40 minutes at room temperature, and thereafter 100ml of water was added to the resulting mixture to terminate thereaction. The precipitate thus formed was filtered, thoroughly washedwith water and recrystallized from acetone. After drying in vacuo, i.e.,5 mmHg, 1.0 g of the product was obtained as a white amorphous solid ina yield of 94 mole%.

In the above reaction, it should be noted that the reaction should becompleted in 20 to 40 minutes after the second addition of chloroacetylchloride. If the reaction is terminated before the above recited time,the starting material, N⁴ -stearoyl-1-β-D-arabinofuranosylcytosine,would remain unreacted. On the other hand, if the reaction is continuedfor more than 40 minutes, the esterification would also proceed at the3'-position. Therefore, as long as the reaction is stopped within theabove recited time range, the desired product wherein only the5'-position is selectively esterified can be obtained at high yield.

Elementary analysis for C₂₉ H₄₈ O₇ N₃ Cl: Calcd. (%): C, 59.42; H, 8.25;O, 19.11; N, 7.17; Cl, 6.05. Found (%): C, 59.52; H, 8.20; O, 19.08; N,7.22; Cl, 6.00.

Ultraviolet absorption spectrum (methanol): λ_(max) : 213 mμ, 248 mμ and299 mμ

Infrared absorption spectrum (KBr): 1733 cm⁻¹ (ester)

EXAMPLE 2

Following the same procedures as described in Example 1 except forvarying the starting materials, the following N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-haloesters were prepared:

N⁴ -Palmitoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate:

Elementary analysis for C₂₇ H₄₄ O₇ N₃ Cl: Calcd. (%): C, 58.10; H, 7.95;O, 20.07, N, 7.53, Cl, 6.35. Found (%): C, 58.22, H, 7.98, O, 20.02, N,7.50, Cl 6.32.

Ultraviolet absorption spectrum (methanol): λ_(max) : 213 mμ, 248 mμ and299 mμ

N⁴ -Margaroyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate:

Elementary analysis for C₂₈ H₄₆ O₇ N₃ Cl: Calcd. (%): C, 58.79; H, 8.10;O, 19.57; N, 7.34; Cl 6.20. Found (%): C, 58.91; H, 8.05; O, 19.42; N,7.41; Cl 6.23.

Ultraviolet absorption spectrum (methanol): λ_(max) : 213 mμ, 248 mμ and299 mμ.

N⁴ -Propionyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Butyryl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Valeryl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Caproyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate. N⁴-Heptanoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Caprylyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Lauroyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Myristoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Tetradecenoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Pentadecanoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Nonadecanoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Arachidoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Behenoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

N⁴ -Lignoceroyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate.

EXAMPLE 3

1.01 g of N⁴ -stearoyl-1-β-D-arabinofuranosylcytosine was dissolved in12 ml of N,N-dimethylacetamide, and 0.27 g of β-chloropropionyl chloridewas added to the solution while ice-cooling, followed by stirring whileice-cooling for 2 hours. 0.27 g of β-chloropropionyl chloride wasadditionally added to the resulting mixture followed by stirring whileice-cooling for 2 hours, and thereafter water was added to the reactionsystem to terminate the reaction. The precipitate formed was filtered,washed with water and then recrystallized from acetone. After drying invacuo, i.e. 5 mmHg, 1.10 g of the product was obtained as a whiteamorphous solid in a yield of 93 mole%.

Elementary analysis for C₃₀ H₅₀ O₇ N₃ Cl: Calcd. (%): C, 60.03; H, 8.40;O, 18.66; N, 7.00; Cl, 5.91. Found (%): C, 60.00; H, 8.38; O, 19.80; N,7.10; Cl, 6.00.

Ultraviolet absorption spectrum (methanol): λ_(max) : 213 mμ, 248 mμ and299 mμ

Infrared absorption spectrum: 1733 cm⁻¹ (ester).

EXAMPLE 4

Following the same procedures as described in Example 3 except forvarying the starting materials, the following N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-haloesters were prepared:

N⁴ -Palmitoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate:

Elementary analysis for C₂₈ H₄₆ O₇ N₃ Cl: Calcd. (%): C, 58.79; H, 8.10;O, 19.57; N, 7.34; Cl, 6.20. Found (%): C, 58.90; H, 8.07; O, 19.38; N,7.42; Cl, 6.22.

Ultraviolet absorption spectrum (methanol): λ_(max) : 213 mμ, 248 mμ and299 mμ

N⁴ -Margaroyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate:

Elementary analysis for C₂₉ H₄₈ O₇ N₃ Cl: Calcd. (%): C, 59.42; H, 8.25;O, 19.11; N, 7.17; Cl, 6.05. Found (%): C, 59.44; H, 8.22; O, 19.08; N,7.22; Cl, 6.08.

Ultraviolet absorption spectrum (methanol): λ_(max) : 213 mμ, 248 mμ and299 mμ

N⁴ -Propionyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Butyryl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Valeryl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Caproyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Heptanoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Caprylyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Lauroyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Myristoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Tetradecenoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Pentadecanoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Nonadecanoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Arachidoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Behenoyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

N⁴ -Lignoceroyl-1-β-D-arabinofuranosylcytosine-5'-chloropropionate.

EXAMPLE 5

3.70 g of diethylamine was added to 0.30 of N⁴-stearoyl-1-β-D-arabinofuranosylcytosine-5'-chloroacetate under anatmosphere of argon followed by stirring for 4 to 5 hours at roomtemperature. After confirming that the raw material had disappeared bythin layer chromatography, the unreacted diethylamine was distilled offunder reduced pressure, i.e., 20 mmHg, under an atmosphere of argon. Thepowder formed was dissolved in absolute diethyl ether, and diethylaminehydrochloride (which is insoluble in diethyl ether) was filtered out.The diethyl ether was distilled off under reduced pressure, i.e., 20mmHg, to provide 0.32 g of a white powder, which was then purified bycolumn chromatography using a column of silica gel to give 0.29 g of awhite powder (yield, 91 mole%).

Elementary analysis for C₃₃ H₅₈ O₇ N₄ : Calcd. (%): C, 63.65; H, 9.37;O, 17.98; N, 9.00. Found (%): C, 63.72; H, 9.33; O, 18.00; N, 9.10.

Ultraviolet absorption spectrum (dioxane): λ_(max) : 248 mμ, and 307 mμ

Infrared absorption spectrum (KBr): 1733 cm⁻¹

Nuclear magnetic resonance spectrum δ(ppm) CDCl₃ : ##STR3##

EXAMPLE 6

Following the same procedures as described in Example 5 except forvarying the starting materials, the following N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-amino esters were obtained:

N⁴ -Palmitoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate:

Elementary analysis for C₃₁ H₅₄ O₇ N₄ : Calcd. (%): C, 62.60; H, 9.15;O, 18.83; N, 9.42. Found (%): C, 62.77; H, 9.12; O, 18.77; N, 9.50.

Ultraviolet absorption spectrum (dioxane): 248 mμ and 307 mμ

N⁴ -Margaroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate:

Elementary analysis for C₃₂ H₅₆ O₇ N₄ : Calcd. (%): C, 63.13; H, 9.27;O, 18.40; N, 9.20. Found (%): C, 63.00; H, 9.25; O, 18.35; N, 9.29.

Ultraviolet absorption spectrum (dioxane): 248 mμ and 307 mμ

N⁴-Stearoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate:

Elementary analysis for C₃₄ H₆₀ O₇ N₄ : Calcd. (%): C, 64.11; H, 9.50;O, 17.59; N, 8.80. Found (%): C, 64.05; H, 9.53; O, 17.71; N, 8.90.

Ultraviolet absorption spectrum (dioxane): 248 mμ and 307 mμ

N⁴-Palmitoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate:

Elementary analysis for C₃₂ H₅₆ O₇ N₄ : Calcd. (%): C, 63.13; H, 9.27;O, 18.40; N, 9.20. Found (%): C, 63.35; H, 9.25; O, 18.29; N, 9.18.

Ultraviolet absorption spectrum (dioxane): 248 mμ and 307 mμ

N⁴-Margaroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate:

Elementary analysis for C₃₃ H₅₈ O₇ N₄ : Calcd. (%): C, 63.65; H, 9.37;O, 17.98; N, 9.00. Found (%): C, 63.67; H, 9.42; O, 18.01; N, 9.03.

Ultraviolet absorption spectrum (dioxane): 248 mμ and 307 mμ.

N⁴ -Propionyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Propionyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Butyryl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Butyryl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Valeryl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Valeryl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Caproyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Caproyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Heptanoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Heptanoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Caprylyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylgylcinate.

N⁴-Caprylyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Lauroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Lauroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Myristoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Myristoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴-Tetradecenoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Tetradecenoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴-Pentadecanoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Pentadecanoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Nonadecanoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Nonadecanoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Arachidoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Arachidoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Behenoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Behenoyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

N⁴ -Lignoceroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylglycinate.

N⁴-Lignoceroyl-1-β-D-arabinofuranosylcytosine-5'-N,N-diethylaminopropionate.

DISPERSIBILITY TEST

The dispersibility of the N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-amino esters according to thisinvention was evaluated by adding 10 mg of the test compound to 1 ml ofwater; the results obtained are shown in Table 1 below.

As is shown in Table 1, the compounds according to the present inventionpossess increased dispersibility in water as compared with the startingmaterial, N⁴ -acyl-1-β-D-arabinofuranosylcytosine.

                                      Table 1                                     __________________________________________________________________________                                      N.sup.4 -acyl-1-β-D-arabino-                                N.sup.4 -acyl-1-β-D-arabino-                                                          furanosylcytosine-5'-                               N.sup.4 -acyl-1-β-D-arabino-                                                          furanosylcytosine-5'-                                                                      N,N-diethylamino-                           N.sup.4 -acyl group                                                                   furanosylcytosine                                                                          N,N-diethylglycinate                                                                       propionate                                  __________________________________________________________________________    propionyl                                                                             dispersed    soluble (10 mg/ml)                                                                         soluble (10 mg/ml)                          butyryl "            soluble ( 5 mg/ml)                                                                         soluble ( 5 mg/ml)                          valeryl floating on surface                                                                        extremely well                                                                             extremely well                                      of water     dispersed    dispersed                                   caproyl "            "            "                                           heptanoyl                                                                             "            "            "                                           caprylyl                                                                              "            "            "                                           lauroyl "            "            "                                           myristoyl                                                                             "            "            "                                           tetradecenoyl                                                                         "            "            "                                           pentadecanoyl                                                                         "            "            "                                           palmitoyl                                                                             "            "            "                                           margaroyl                                                                             "            "            "                                           stearoyl                                                                              "            "            "                                           nonadecanoyl                                                                          "            "            "                                           arachidoyl                                                                            "            "            "                                           behenoyl                                                                              "            "            "                                           __________________________________________________________________________

BIOLOGICAL TEST

The anti-cancer activity of the novel compounds, N⁴-acyl-1-β-D-arabinofuranosylcytosine-5'-amino esters, according to thepresent invention was determined as follows: 100,00 cells/mouse ofL-1210 leukemia were administered by intraperitoneal injection to groupsof CDF₁ male mice (3 mice per group), and, after 2 days and after 6days, a physiological saline solution containing the test material in anamount of 100, 200 or 400 mg/Kg was administered by intraperitonealinjection to the mice. Further, a physiological saline solutioncontaining no test material was similarly administered to the miceinfected with L-1210 leukemia for comparison purposes.

The anti-cancer activity of the test material was evaluated by means ofsurvival rate comparison, T/C (%), that is, 100 times the mean survivalperiod of the groups injected with the test material divided by the meansurvival period of the comparison groups which were not injected withthe test material.

According to this evaluation, a survival rate comparison, T/C (%), oflower than 100% indicates that the test material is toxic, and one ofhigher than 125% indicates that the test material possesses therapeuticeffects. As will be seen from the results given in Table 2 below, amongthe compounds of this invention, those wherein the N⁴ -acyl group has 14to 22 carbon atoms exhibited a high survival rate at a lowconcentration, and, therefore, are particularly useful.

                                      Table 2                                     __________________________________________________________________________              N.sup.4 -acyl-1-β-D-arabino-                                                            N.sup.4 -acyl-1-β-D-arabino-                              furanosylcytosine-5'-                                                                        furanosylcytosine-5'-                                          N,N-diethylglycinate                                                                         N,N-diethylaminopropionate                                     T/C (%)        T/C (%)                                              N.sup.4 -acyl                                                                           400  200  100  400  200  100                                        group     (mg/Kg)                                                                            (mg/Kg)                                                                            (mg/Kg)                                                                            (mg/Kg)                                                                            (mg/Kg)                                                                            (mg/Kg)                                    __________________________________________________________________________    propionyl 130  125  125  128  120  120                                        butyryl   132  127  127  132  125  120                                        valeryl   132  130  127  130  130  119                                        caproyl   140  133  125  133  123  125                                        heptanoyl 143  127  123  141  132  127                                        caprylyl  200  182  140  202  181  135                                        lauroyl   225  201  170  212  173  141                                        myristoyl  90  192  278   93  182  281                                        tetradecenoyl                                                                            91  309  250   99  288  230                                        pentadecanoyl                                                                            95  305  320   95  310  340                                        palmitoyl  99  280  349  125  340  381                                        margaroyl 120  279  390  111  321  388                                        stearoyl  140  244  355  140  315  344                                        nonadecanoyl                                                                            120  260  298  120  280  295                                        arachidoyl                                                                              303  362  300  311  351  299                                        behenoyl  341  298  260  321  288  250                                        lignoceroyl                                                                             120  125  127  115  127  131                                        1-β-D-arabino-      150  130  110                                        furanosylcytosine                                                             __________________________________________________________________________

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A nucleoside derivative represented by the formula: ##STR4##wherein R¹ represents an acyl group having 3 to 28 carbon atoms and R² represents an XCH₂ -, XCH₂ CH₂ -- or CH₃ CHX-group, wherein X represents chloro, bromo, a (CH₃)₂ N-group or a (C₂ H₅)₂ N-group.
 2. A nucleoside derivative represented by the formula: ##STR5##wherein R¹ represents an acyl group having 14 to 22 carbon atoms and R² represents an XCH₂ --, XCH₂ CH₂ -- or CH₃ CHX-group, wherein X represents chloro, bromo, a (CH₃)₂ N-group or a (C₂ H₅)₂ N-group.
 3. The nucleoside derivative as claimed in claim 2, wherein said acyl group is myristoyl, tetradecenoyl, pentadecanoyl, palmitoyl, margaroyl, stearoyl, nonadecanoyl, arachiodoyl or behenoyl.
 4. The nucleoside derivative as claimed in claim 1, wherein said X represents a (CH₃)₂ N-group or a (C₂ H₅)₂ N-group.
 5. The nucleoside derivative as claimed in claim 4, wherein said acyl group is myristoyl, tetradecenoyl pentadecanoyl, palmitoyl, margaroyl, stearoyl, nonadecanoyl, arachiodoyl or behenoyl. 